PB2130: RATIONAL FOR METHOTREXATE USAGE FOR THE TREATMENT AND PREVENTION OF CNS INVOLVEMENT IN PATIENTS WITH HIGH-GRADE B-CELL LYMPHOMAS.
Authors: A. Misyurina, S. Kravchenko, A. Magomedova, A. Kovrigina, T. Obukhova, K. Sychevskaya, F. Babaeva
Journal: HemaSphere (2022)

Background: The role of methotrexate-containing prophylaxis (MTX-CP) still to be discussed due to high-rate of primary resistance of high-grade B-cell lymphoma (HGBL) for intensive and conventional treatment. In several cases HGBLs are represented by transformed low-grade lymphomas (LGL) (follicular or marginal zone). Despite of high-dose methotrexate (HD-MTX) has better pharmacodynamics in cerebrospinal fluid than endolumbar methotrexate given with endolumbar triplet injections (ETI), it couldn’t be prescribed in some cases due to old age and comorbidities. Aims: To characterise patients with CNS-involvment and to estimate the role of MTX-CP. Methods: We had data about CNS involvement relating 91 pts with HGBLs (48 pts with HGBL NOS, 22 – c-MYC/BCL2 HGBL DH, 6 - HGBL TH, 15 - c-MYC/BCL6 HGBL) which were treated in National Research Center for Hematology, Moscow, Russia in the period from 2008 till 2022 years. The majority of pts (71/86 (83%)) had IPI score 3-5. Till 2018 year we used Burkitt-like regimens similar as CODOX-M/IVAC or Hyper-CVAD in young and fit patients to treat HGBL DH or NOS. Since 2018 year it was initiated randomized prospective trail «R-Burkitt Lymphoma-Moscow-04 Versus R-(DA)-EPOCH and Autologous Stem Cells Transplantation in Patients With High-Grade B-cell Lymphoma Double-hit (HGBL DH) and High-Grade B-cell Lymphoma Not Otherwise Specified (HGBL NOS)», NCT03479918. We suggested an integral transformation index (ITI) indicating the probability of HGBL development from LGL (EHA-1767). Statistical analysis was performed in STATISTICA 12.0 software. Compassion of groups were carried out using χ2 test. Differences were considered as significant at p-value < 0.05. Results: The majority of pts had CNS prophylaxis/treatment with HD-MTX (1,0-1,5 g/m2)) which was administered in 51/89 of pts (57%), 26/89 (29%) of pts had both HD-MTX and ETI; 22/89 (25%) of pts had ETI only; 18/89 (20 %) of pts had no prophylaxis, p<0,001. CNS-IPI score was high in 12/18 (67%) of pts without CNS-prophylaxis, in 31/51 of pts (61%) with HD-MTX-containing prophylaxis, in 16/22 of pts (72%) with ETI (p>0,05). CNS involvement at the time of disease onset was revealed in pts received HD-MTX-containing therapy in 10/51 of pts (20%), in 6/22 of pts with ETI (27%) (5 pts had leptomeningeal involvement and one elderly patient had foci in brain and ECOG 3). ITI score at least 1 point was revealed in 24/25 of pts (96%) with CNS involvement and 43/68 of pts (63%) without, p=0,002. CNS involvement was strongly associated with bone marrow infiltration, p<0,001. Rate of CNS involvement due to relapse or disease progression was following – 4/51 (8%) of pts in the HD-MTX-group, 1/22 (5%) of pts – in the ETI-group, 5/17 (29%) of pts without any prophylaxis. Despite HD-MTX prophylaxis failure in 8 % of pts it decreased significally the probability of CNS relapse, p=0,02. ETI also showed benefit in treatment of leptomeningeal involvement and prophylaxis of relapse into CNS compared with absence of any prophylaxis, p=0,04. Summary/Conclusion: CNS involvement was strongly associated with bone marrow infiltration and probability of HGBL development from low-grade lymphoma. MTX-CP showed benefit in treatment of CNS involvement in HGBLs. Cases of relapses could be explained by methotrexate-resistance due to intrinsic mechanisms of tumor development.